ABSTRACT Recent outbreaks of Zika virus infections linked to neonatal birth defects have generated immense concerns and widespread efforts to halt virus spread. Flaviviruses like Zika and West Nile Virus (WNV) share considerable homology not only in their genome organization, virion structure but also the nature of elicited immune response. In this regard, studies have shown that prior vaccination against one Flavivirus like Tick Borne Encephalitis Virus (TBEV) provides cross protection against a heterologous Flavivirus like Japanese Encephalitis Virus (JEV). This is mainly due to the presence of cross reacting neutralizing antibodies directed against the Envelope glycoprotein of the virus. On the contrary, preexisting immune response against a Flavivirus may also lead to exaggerated disease, a phenomenon commonly seen in Dengue virus infections known as Antibody Dependent Enhancement (ADE). Flavivirus infections are mainly transmitted by mosquito bites and in the El Paso border area both Aedes aegypti and Aedes albopictus species of mosquito vectors exist that are capable of transmitting both WNV and Zika. While WNV infections are regularly reported in El Paso, 80% of the WNV infections worldwide result in mild symptoms and hence remain undiagnosed. Thus, prevalence of antibodies in the population especially in WNV endemic areas like El Paso would be much higher than the reported cases. This raises the question as to how prevalence of preexisting antibodies to WNV may modulate infection by Zika virus. Our study will help address this question by 1) Surveilling for the presence of WNV and Zika virus antibodies from volunteers in El Paso and obtaining blood samples from targeted patients previously reported by the Department of Public Health to be positive for WNV infection. 2) Use a novel GFP based microneutralization assay to determine whether preexisting antibodies to WNV modulate Zika virus infection. These studies will help gain fundamental insights regarding Zika virus immunobiology and modulation Zika virus infection via heterologous antibodies. This will aid in the efforts towards development of effective Zika vaccines and therapeutics.